3D,2D-QSAR study and docking of novel quinazolines as potential target drugs for osteosarcoma

Abstract

Background: Quinazolines are an important class of benzopyrimidine heterocyclic compounds with a promising antitumor activity that can be used for the design and development of osteosarcoma target compounds.Objective: To predict the compound activity of quinazoline compounds by constructing 2D- and 3D-QSAR models, and to design new compounds according to the main influencing factors of compound activity in the two models.Methods: First, heuristic method and GEP (gene expression programming) algorithm were used to construct linear and non-linear 2D-QSAR models. Then a 3D-QSAR model was constructed using CoMSIA method in SYBYL software package. Finally, new compounds were designed according to molecular descriptors of 2D-QSAR model and contour maps of 3D-QSAR model. Several compounds with optimal activity were used for docking experiments with osteosarcoma related targets (FGFR4).Results: The non-linear model constructed by GEP algorithm was more stable and predictive than the linear model constructed by heuristic method. A 3D-QSAR model with high Q2 (0.63) and R2 (0.987) values and low error values (0.05) was obtained in this study. The success of the model fully passed the external validation formula, proving that the model is very stable and has strong predictive power. 200 quinazoline derivatives were designed according to molecular descriptors and contour maps, and docking experiments were carried out for the most active compounds. Compound 19g.10 has the best compound activity with good target binding capability.Conclusion: To sum up, the two novel QSAR models constructed were very reliable. The combination of descriptors in 2D-QSAR with COMSIA contour maps provides new design ideas for future compound design in osteosarcoma.

Design of New Second‐Generation TRK Inhibitors Targeting Tropomyosin Receptor Kinases by Using Molecular Docking, Molecular Dynamics Simulations and ADMET Properties

“…In the CoMFA (Comparative Molecular Field Analysis) model, optimized molecules are placed within a standard three-dimensional grid with a step size set at 2 Å. [22] A positively charged sp 3 hybridized carbon cation is used as a probe atom to calculate the energy of the steric field (S) and electrostatic field (E) using the Tripos force field. The interaction energy between each probe particle and the molecules is also computed to detect the field effects around small molecules.…”

Design, synthesis and antitumor activity evaluation in vitro of 4,6,7-trisubstituted quinazoline derivatives containing acrylamide moiety

“…Quinazoline is a nitrogen-containing bicyclic compound of benzopyrimidine, widely present in various organic compounds with excellent biological activity [7][8][9]. Compounds 1 [10], 2 [11], 3 [12], and 4 [13] are quinazoline derivatives with anti-tumor, antimalarial, antiviral, and anti-high blood pharmacological activities.…”